PHARMACEUTICAL AGENT COMPRISING QUINOLONE COMPOUND
The present invention provides a pharmaceutical agent that inhibits the chronic progression of Parkinson's disease or protects dopamine neurons from disease etiology, thereby suppressing the progression of neurological dysfunction, so as to prolong the period of time until L-dopa is administered while also improving neuronal function; the pharmaceutical agent of the invention comprising as an active ingredient a quinolone compound represented by Formula (1): or a salt thereof, wherein: R1 represents hydrogen or the like; R2 represents hydrogen or the like; R3 represents substituted or unsubstituted phenyl or the like; R4 represents hydrogen or the like; R5 represents hydrogen or the like; R6 represents hydrogen or the like; and R7 represents hydroxy or the like.
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The present invention relates to a therapeutic and/or prophylactic agent for neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases induced by deterioration of mitochondrial function, the agent comprising a quinolone compound or a salt thereof as an active ingredient.
BACKGROUND ARTParkinson's disease is a chronic, progressive neurodegenerative disease that generally develops after middle age. Initial symptoms include unilateral resting tremor, akinesia and rigidity. The tremors, akinesia, and rigidity are called the three major signs of Parkinson's disease, and each of them is caused by the selective death of dopaminergic neurons projected from the substantia nigra to the striatum. The etiology of the disease is still unknown; however, accumulated evidence suggests that an impaired energy-generating system accompanied by abnormal mitochondrial function of nigrostriatal dopaminergic neurons triggers the neurodegenerative disorder of the disease. The mitochondrial dysfunction has been assumed to subsequently cause oxidative stress and failure of calcium homeostasis, thereby resulting in neurodegeneration (NPL 1).
Treatments of Parkinson's disease are roughly classified into medical management (medication) and surgical management (stereotaxic operation). Of these, medication is an established therapy and regarded as a basic treatment. In the medication, a symptomatic therapeutic agent is used to compensate for the nigrostriatal dopaminergic neuronal function denatured by Parkinson's disease. L-dopa exhibits the most remarkable therapeutic effects. It is said that no agent exceeds the effectiveness of L-dopa. Currently, L-dopa is used together with a dopa decarboxylase inhibitor to prevent the metabolism thereof in the periphery, and the desired clinical effects have been obtained.
However, L-dopa treatment has drawbacks in that, after several years of usage, there is a recurrence of movement disorders such as dyskinesia, and the sustainability and stability of the drug's effects are lost, resulting in fluctuations within each day. Moreover, side effects including digestive problems such as nausea and vomiting brought on by excessive release of dopamine, circulatory organ problems such as orthostatic hypotension, tachycardia and arrhythmia, and neurological manifestations such as hallucination, delusion and distraction have been a cause for concern.
Thus, in order to decrease the L-dopa preparation dosage and thereby reduce the side effects, multidrug therapies, in which dopamine receptor agonists, dopamine metabolism enzyme inhibitors, dopamine releasers, central anticholinergic agents and the like are used in combination, are employed. While such therapeutic advances remarkably improve prognoses, there is still no fundamental cure for Parkinson's disease and other neurodegenerative diseases. Medication must be taken for the rest of the patient's life, and the aforementioned drawbacks, i.e., decreased efficacy during long-term administration, side effects, and uncontrollable disease progression, can result from L-dopa monotherapy. In addition, it is difficult to expect dramatic effects, even with the employment of multidrug therapies.
Alzheimer's disease is a progressive neurodegenerative disease that affects various cognitive functions, primarily causing impairment of memory. Pathologically, Alzheimer's disease is characterized by the degeneration of synapses or neurons in the hippocampus and cerebral cortex, and the accumulation of two types of abnormal fibrils, i.e., senile plaques and changes in neurofibrils. Although the disease etiology is not completely understood, amyloid β protein (Aβ), which is derived from amyloid precursor protein (APP) by various mechanisms, is known to play an important role. Currently, cholinesterase inhibitors (tacrine, Aricept, rivastigmine, and galantamine) are used in the treatment of Alzheimer's disease for ameliorating symptoms, because acetylcholinergic nervous system in the brain is involved in cognitive function, and marked deficits in the acetylcholinergic system are observed in Alzheimer's disease. N-methyl-D-aspartate glutamate receptor antagonists (memantine) are also in practical use because hyperexcitability of the mechanism of glutamate neurotransmission is associated with neural degeneration or impairment. Neither monotherapy nor combination therapy using these drugs, however, has produced sufficient therapeutic effects, nor are they capable of halting the progression of the disease. Furthermore, gastrointestinal symptoms such as nausea and diarrhea are observed as side effects of cholinesterase.
With respect to ischemic neurodegenerative disorders induced by cerebral infarctions, such as atherothrombotic cerebral infarction, lacunar infarction, cardiogenic cerebral embolism, etc., the usage of very early thrombolytic therapy using tissue plasminogen activator (tPA) is rapidly increasing. This therapy, however, has many problems including a time window as short as within three hours after the onset of disease, hemorrhagic complications, etc.
In Japan, a free radical scavenger, edaravone, is used for a brain protection therapy. Although edaravone can be used concomitantly with tPA, sufficient clinical results have not been obtained.
Accordingly, there exists a strong need for a pharmaceutical agent having a novel mechanism of action, or a neuroprotectant for preventing neural degeneration or impairment from its etiologies such as abnormal mitochondrial function, etc.
PTL 1 discloses a quinolone compound or a salt thereof that is effective as an anticancer agent; however, PTL 1 does not teach that the compound or a salt thereof is effective as a therapeutic and/or prophylactic agent for neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases induced by deterioration of mitochondrial function.
Additionally, PTL 2 discloses a quinolone compound that is effective for preventing intimal proliferation; however, PTL 2 but does not teach that the compound is effective as a therapeutic and/or prophylactic agent for neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases induced by deterioration of mitochondrial function.
CITATION LIST Patent Literature
- PTL 1: WO 2001/012607
- PTL 2: WO 2002/022074
- NPL 1: Anna N.Y. Acad. Sci. 991: 111-119 (2003)
An object of the present invention is to provide a therapeutic and/or prophylactic agent that inhibits the chronic progression of Parkinson's disease or protects dopamine neurons from the disease itself, thereby suppressing the progression of neurological dysfunction, so as to prolong the period of time until L-dopa is administered while also improving neuronal function.
Another object of the invention is to provide a pharmaceutical agent that is useful in treating diseases that induce cell death, and more specifically, to provide a pharmaceutical agent having efficacy for treating Alzheimer's disease, or improving dysfunction or neurologic deficits induced by cerebral apoplexy.
Solution to ProblemThe present inventors conducted extensive research to accomplish the aforementioned object. Consequently, they succeeded in producing a compound represented by Formula (1) shown below, which protects and improves mitochondrial function, and/or protects neurons and repairs neuronal function. The present invention has been accomplished based on the above findings.
The invention provides a therapeutic and/or prophylactic agent comprising a quinolone compound and a method for treating and/or preventing diseases as set forth in the following Items 1 to 6.
Item 1. A therapeutic and/or prophylactic agent for neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases induced by deterioration of mitochondrial function, the agent comprising as an active ingredient a quinolone compound represented by Formula (1):
or a salt thereof, wherein:
R1 represents hydrogen, lower alkyl, or cyclo C3-C8 alkyl lower alkyl;
R2 represents hydrogen or lower alkyl; and
R3 represents phenyl, naphthyl, pyridyl, furyl, thienyl, indolyl, benzodioxolyl or benzothienyl, wherein the aromatic or heterocyclic ring represented by R3 may be substituted with one or more substituents selected from the group consisting of the following substituents (1) to (7):
(1) lower alkyl,
(2) halogen-substituted lower alkyl,
(3) hydroxy,
(4) lower alkoxy,
(5) halogen-substituted lower alkoxy,
(6) phenyl optionally having one or more substituents selected from the group consisting of lower alkyl and lower alkoxy, and
(7) halogen;
R4 represents hydrogen, lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkoxy, lower alkoxy lower alkyl, phenyl, cyclo C3-C8 alkyl, or carbamoyl optionally having one or two lower alkyl groups;
R5 represents hydrogen, lower alkyl, halogen, lower alkoxy, benzoylamino, or imidazolyl,
R6 represents hydrogen, halogen, lower alkyl, hydroxy, or lower alkoxy; and
R7 represents any of the following groups (1) to (19):
(1) hydrogen,
(2) hydroxy,
(3) lower alkyl,
(4) lower alkoxy,
(5) phenoxy,
(6) cyclo C3-C8 alkyloxy,
(7) halogen,
(8) lower alkylthio,
(9) amino optionally having one or two substituents selected from the group consisting of lower alkyl, lower alkoxy lower alkyl, and cyclo C3-C8 alkyl,
(10) carbamoyl optionally having one or two lower alkyl groups,
(11) pyrrolidinyl,
(12) azepanyl,
(13) morpholinyl,
(14) piperazinyl optionally having one or two lower alkyl groups,
(15) imidazolyl optionally having one or two lower alkyl groups,
(16) furyl,
(17) thienyl,
(18) benzothienyl, and
(19) pyrrolidinylcarbonyl.
Item 2. A therapeutic and/or prophylactic agent according to Item 1, wherein the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Parkinson's syndrome, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear palsy, pure akinesia, Alzheimer's disease, Pick's disease, prion disease, corticobasal degeneration, diffuse Lewy body disease, Huntington's disease, chorea-acanthocytosis, benign hereditary chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, Gilles de la Tourette's syndrome, Rett's syndrome, degenerative ballism, dystonia musculorum deformans, athetosis, spasmodic torticollis, Meige syndrome, cerebral palsy, Wilson's disease, Segawa's disease, Hallervorden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy, spinocerebellar degeneration, cerebral cortical atrophy, Holmes-type cerebellar atrophy, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, Joseph disease, dentatorubropallidoluysian atrophy, Gerstmann-Straussler-Scheinker disease, Friedreich's ataxia, Roussy-Levy syndrome, May-White syndrome, congenital cerebellar ataxia, hereditary episodic ataxia, ataxia telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, spinal progressive muscular atrophy, spinobulbar muscular atrophy, Werdnig-Hoffmann disease, Kugelberg-Welander disease, hereditary spastic paraparesis, syringomyelia, syringobulbia, Arnold-Chiari malformation, Stiff-man syndrome, Klippel-Feil syndrome, Fazio-Londe syndrome, lower myelopathy, Dandy-Walker syndrome, spina bifida, Sjogren-Larsson syndrome, radiation myelopathy, age-related macular degeneration, and cerebral apoplexy selected from the group consisting of cerebral infarction and cerebral hemorrhage and/or associated dysfunction or neurologic deficits.
Item 3. A therapeutic and/or prophylactic agent according to Item 1, wherein the disease induced by neurological dysfunction is selected from the group consisting of spinal cord injury, chemotherapy-induced neuropathy, diabetic neuropathy, radiation damage, and a demyelinating disease selected from the group consisting of multiple sclerosis, acute disseminated encephalomyelitis, transverse myelitis, progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis, chronic inflammatory demyelinating polyneuropathy, and Guillain-Barre syndrome.
Item 4. A therapeutic and/or prophylactic agent according to Item 1, wherein the disease induced by deterioration of mitochondrial function is selected from the group consisting of Pearson's syndrome, diabetes, deafness, malignant migraine, Leber's disease, MELAS, MERRF, MERRF/MELAS overlap syndrome, NARP, pure myopathy, mitochondrial cardiomyopathy, myopathy, dementia, gastrointestinal ataxia, acquired sideroblastic anemia, aminoglycoside-induced hearing loss, complex III deficiency due to inherited variants of cytochrome b, multiple symmetric lipomatosis, ataxia, myoclonus, retinopathy, MNGIE, ANT1 disease, Twinkle disease, POLG disease, recurrent myoglobinuria, SANDO, ARCO, complex I deficiency, complex II deficiency, optic nerve atrophy, fatal infantile complex IV deficiency, mitochondrial DNA deficiency syndrome, Leigh's encephalomyelopathy, chronic progressive external ophthalmoplegia syndrome (CPEO), Kearns-Sayre syndrome, encephalopathy, lactacidemia, myoglobinuria, drug-induced mitochondrial diseases, schizophrenia, major depression disorder, bipolar I disorder, bipolar II disorder, mixed episode, dysthymic disorders, atypical depression, seasonal affective disorders, postpartum depression, minor depression, recurrent brief depressive disorder, intractable depression, chronic depression, double depression, and acute renal failure.
Item 5. A therapeutic and/or prophylactic agent comprising as an active ingredient a quinolone compound represented by Formula (1) of Item 1 or a salt thereof, the agent being used for treating or preventing ischemic heart diseases and/or associated dysfunction, cardiac failure, myocardosis, aortic dissection, immunodeficiency, autoimmune diseases, pancreatic insufficiency, diabetes, atheroembolic renal disease, polycystic kidney, medullary cystic disease, renal cortical necrosis, malignant nephrosclerosis, renal failure, hepatic encephalopathy, liver failure, chronic obstructive pulmonary disease, pulmonary embolism, bronchiectasis, silicosis, black lung, idiopathic pulmonary fibrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, muscular dystrophy, clostridial myonecrosis, and femoral condyle necrosis.
Item 6. A method for treating and/or preventing neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases induced by deterioration of mitochondrial function, the method comprising administering a quinolone compound represented by Formula (1) of Item 1 or a salt thereof to a human or an animal.
Each group in Formula (1) is specifically described below.
The term “lower” refers to a group having 1 to 6 carbons (preferably 1 to 4 carbons), unless otherwise specified.
Examples of lower alkyl groups include straight or branched C1-6 (preferably C1-4) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1,2,2-trimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, isohexyl, 3-methylpentyl, etc.
Examples of cyclo C3-C8 alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
Examples of cyclo C3-C8 alkyl lower alkyl groups include the lower alkyl groups having one to three (preferably one) cyclo C3-C8 alkyl group(s) described above.
Examples of lower alkoxy groups include straight or branched C1-6 (preferably C1-4) alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy, etc.
Examples of lower alkoxy lower alkyl groups include the lower alkyl groups having one to three (preferably one) lower alkoxy group(s) described above.
Examples of halogen atoms include fluorine, chlorine, bromine, and iodine.
Examples of halogen-substituted lower alkyl groups include the lower alkyl groups having one to seven halogen atom(s), preferably one to three halogen atom(s). Examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, dichlorofluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoroethyl, 2-chloroethyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoroisopropyl, 3-chloropropyl, 2-chloropropyl, 3-bromopropyl, 4,4,4-trifluorobutyl, 4,4,4,3,3-pentafluorobutyl, 4-chlorobutyl, 4-bromobutyl, 2-chlorobutyl, 5,5,5-trifluoropentyl, 5-chloropentyl, 6,6,6-trifluorohexyl, 6-chlorohexyl, perfluorohexyl, etc.
Examples of halogen-substituted lower alkoxy groups include the lower alkoxy groups having one to seven halogen atom(s), preferably one to three halogen atom(s). Examples thereof include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, bromomethoxy, dibromomethoxy, dichlorofluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2-chloroethoxy, 3,3,3-trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy, 3-chloropropoxy, 2-chloropropoxy, 3-bromopropoxy, 4,4,4-trifluorobutoxy, 4,4,4,3,3-pentafluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy, 2-chlorobutoxy, 5,5,5-trifluoropentoxy, 5-chloropentoxy, 6,6,6-trifluorohexyloxy, 6-chlorohexyloxy, etc.
Examples of lower alkylthio groups include alkylthio groups wherein the alkyl moiety is the lower alkyl group mentioned above.
Examples of phenyl groups optionally having one or more substituents selected from the group consisting of lower alkyl and lower alkoxy include phenyl groups optionally having one to three (preferably one or two) group(s) selected from the group consisting of the lower alkyl groups and the lower alkoxy groups described above.
Examples of carbamoyl groups optionally having one or more lower alkyl groups include carbamoyl groups optionally having one or two lower alkyl groups described above.
Examples of amino groups optionally having one or two substituents selected from the group consisting of lower alkyl groups, lower alkoxy lower alkyl groups, and cyclo C3-C8 alkyl groups include amino groups optionally having one or two groups selected from the group consisting of the lower alkyl groups, the lower alkoxy lower alkyl groups, and the cyclo C3-C8 alkyl groups described above.
Examples of piperazinyl groups optionally having one or two lower alkyl groups include piperazinyl groups optionally having one or two (preferably one) lower alkyl group(s) described above.
Examples of imidazolyl groups optionally having one or two lower alkyl groups include imidazolyl groups optionally having one or two (preferably one) lower alkyl group(s) described above.
Examples of lower alkoxy lower alkyl groups include the lower alkyl groups having one to three (preferably one) lower alkoxy group(s) described above.
Examples of cyclo C3-C8 alkyloxy groups include groups in which the cyclo C3-C8 alkyl groups described above are bonded to an oxygen atom.
The process of producing the compound of the invention is described below in detail.
The quinolone compound represented by Formula (1) (hereinafter also referred to as Compound (1)) can be produced by various methods; for example, by a method according to the following Reaction Scheme 1.
wherein R1, R2, R3, R4, R5, R6, and R7 are as defined above, and R8 represents a lower alkoxy group.
The lower alkoxy group represented by R8 in Formula (3) has the same definition as described above.
The compound represented by Formula (2) is reacted with the compound represented by Formula (3) in an inert solvent or without using any solvents, in the presence or absence of an acid catalyst, thereby giving an intermediate compound represented by Formula (4). Then, the resulting compound is cyclized to produce the compound represented by Formula (1).
Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; lower alcohols such as methanol, ethanol, and isopropanol; and polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile. These inert solvents can be used singly or in combinations of two or more.
Various kinds of known acid catalysts can be used, including toluenesulfonic acid, methanesulfonic acid, xylene sulfonic acid, sulfuric acid, glacial acetic acid, boron trifluoride, acidic ion exchangers, etc. These acid catalysts can be used singly or in combinations of two or more.
Among such acids, acidic ion exchangers are preferably used. Examples of acidic ion exchangers include polymeric cation exchangers available from the market such as Lewatit S100, Zeo-karb 225, Dowex 50, Amberlite IR120, or Amberlyst 15 and like styrene sulfonic acid polymers; Lewatit PN, Zeo-karb 215 or 315, and like polysulfonic acid condensates; Lewatit CNO, Duolite CS100, and like m-phenolic carboxylic acid resins; or Permutit C, Zeo-karb 226 or Amberlite IRC 50, and like polyacrylates. Of these, Amberlyst 15 is particularly preferred.
An acid catalyst is usually used in an amount of 0.0001 to 100 moles, preferably 0.5 to 6 moles, per mole of the compound of Formula (2).
In Reaction Scheme 1, the compound of Formula (3) is usually used in an amount of at least about 1 mole, preferably about 1 to about 5 moles, per mole of the compound of Formula (2).
The reaction can be conducted under normal pressure, under inert gas atmospheres including nitrogen, argon, etc., or under increased pressure.
The reaction proceeds usually at room temperature to 200° C., and preferably at room temperature to 150° C. During the reaction, azeotropic removal of water is conducted until the reaction water generation is completed. The reaction is usually finished in about 1 to about 30 hours.
The process of producing the compound of Formula (1) via a cyclization reaction of the intermediate compound represented by Formula (4) can be carried out by heating the compound in a solvent such as diphenyl ether, or by heating the compound in the absence of a solvent. The reaction is conducted at 150 to 300° C. for 5 minutes to 2 hours.
The compound represented by Formula (2), used as a starting material in Reaction Scheme 1, is a known compound or can be produced easily using a known compound. The compound represented by Formula (3) includes a novel compound, and the compound is manufactured in accordance with, for example, the method shown in Reaction Scheme 2 described below.
wherein R2, R3, and R8 are as defined above, and R9 represents a lower alkoxy group.
The lower alkoxy group represented by R9 in Formula (6) has the same definition as described above.
The compound represented by Formula (3) can be produced by the reaction of the compound represented by Formula (5) with the compound represented by Formula (6) in an inert solvent or without using any solvents, in the presence or absence of a basic compound.
Examples of inert solvents include water; ethers such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatic hydrocarbons such as benzene, toluene, and xylene; lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; and polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, and acetonitrile. These inert solvents can be used singly or in combinations of two or more.
As a basic compound, various known inorganic bases and organic bases can be used.
Inorganic bases include, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; alkali metals such as sodium and potassium; amides such as sodium amide; and alkali metal hydrides such as sodium hydride and potassium hydride.
Organic bases include, for example, alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, and potassium t-butoxide; and amines such as triethylamine, tripropylamine, pyridine, quinoline, piperidine, imidazole, N-ethyl diisopropylamine, dimethylaminopyridine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.
Such basic compounds can be used singly or in combinations of two or more. More preferable basic compounds used in the reaction include inorganic bases such as sodium hydride and potassium hydride.
A basic compound is usually used in an amount of 1 to 10 moles, preferably 1 to 6 moles, per mole of the compound of Formula (5).
In Reaction Scheme 2, the compound of Formula (6) is usually used in an amount of at least about 1 mole, preferably 1 to about 5 moles, per mole of the compound of Formula (5).
The reaction can be conducted under normal pressure, under inert gas atmospheres including nitrogen, argon, etc., or under increased pressure.
The reaction proceeds usually at room temperature to 200° C., and preferably at room temperature to 150° C., and is usually completed in about 1 to about 30 hours.
The compounds represented by Formulae (5) and (6), which are used as starting materials in Reaction Scheme 2, are easily available known compounds.
The raw material compounds used in each of the reaction schemes described above may include suitable salts, and the objective compounds obtained via each of the reactions may form suitable salts. These preferable salts include the following preferable salts of Compound (1).
Suitable salts of Compound (1) are pharmacologically allowable salts including, for example, salts of inorganic bases such as metal salts including alkali metal salts (e.g., sodium salts, potassium salts, etc.) and alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.), ammonium salts, alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal hydrogencarbonates (e.g., lithium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), and alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); salts of organic bases such as tri(lower)alkylamine (e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower)alkyl-morpholine (e.g., N-methylmorpholine, etc.), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO); inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and organic acid salts such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, and glutamate.
In addition, compounds in a form in which a solvate (for example, hydrate, ethanolate, etc.) was added to the starting materials and the objective compound shown in each of the reaction schemes are also included in each of the general formulae. Hydrate can be mentioned as a preferable solvate.
Each of the objective compounds obtained according to the above reaction schemes can be isolated and purified from the reaction mixture by, for example, cooling the reaction mixture, first, performing an isolation procedure such as filtration, concentration, extraction, etc., to separate a crude reaction product, and then subjecting the crude reaction product to a usual purification procedure such as column chromatography, recrystallization, etc.
The compound represented by Formula (1) according to the present invention naturally includes geometrical isomers, stereoisomers, optical isomers, and like isomers.
The following points should be noted regarding the compound of Formula (1) shown above. Specifically, when R1 of Formula (1) represents a hydrogen atom, the compound includes a tautomer of the quinolone ring. That is, in the quinolone compound of Formula (1), when R1 represents a hydrogen atom (1′),
wherein R2, R3, R4, R5, R6, and R7 are as defined above, the compound of the tautomer can be represented by Formula (1″),
wherein R2, R3, R4, R5, R6, and R7 are as defined above. That is, both of the compounds represented by Formulae (1′) and (1″) are in the tautomeric equilibrium state represented by the following balance formula.
wherein R2, R3, R4, R5, R6, and R7 are as defined above.
Such tautomerism between a 4-quinolone compound and a 4-hydroxyquinoline compound is technically known, and it is obvious for a person skilled in the art that both of the above-described tautomers are balanced and mutually exchangeable.
Therefore, the compound represented by Formula (1) of the present invention naturally includes the tautomers as mentioned above.
In the specification, the constitutional formula of a 4-quinolone compound is suitably used as a constitutional formula of the objective or starting material including compounds of such tautomers.
The present invention also includes isotopically labeled compounds that are identical to the compounds represented by Formula (1), except that one or more atoms are replaced by one or more atoms having specific atomic mass or mass numbers. Examples of isotopes that can be incorporated into the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, and 36Cl. Certain isotopically labeled compounds of the present invention, which include the above-described isotopes and/or other isotopes of other atoms, for example, those into which radioisotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assay. Tritiated (i.e., 3H), and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, an increased in vivo half-life or reduced dosage requirements. The isotopically labeled compounds of the present invention can generally be prepared by substituting a readily available, isotopically labeled reagent for a non-isotopically labeled reagent according to the method disclosed in the schemes above and/or in the Examples below.
The compound of Formula (1) and the salt thereof are used in the form of general pharmaceutical preparations. The preparations are obtained using typically employed diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrators, surfactants, lubricants, etc. The form of such pharmaceutical preparations can be selected according to the purpose of the therapy. Typical examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), and the like.
To form tablets, any of various carriers conventionally known in this field can be used. Examples thereof include lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and other excipients; water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, and other binders; dry starch, sodium alginate, agar powder, laminarin powder, sodium hydrogen carbonate, calcium carbonate, fatty acid esters of polyoxyethylene sorbitan, sodium lauryl sulfate, stearic acid monoglycerides, starch, lactose, and other disintegrators; white sugar, stearin, cacao butter, hydrogenated oils, and other disintegration inhibitors; quaternary ammonium bases, sodium lauryl sulfate, and other absorption promoters; glycerol, starch, and other wetting agents; starch, lactose, kaolin, bentonite, colloidal silicic acid, and other adsorbents; purified talc, stearates, boric acid powder, polyethylene glycol, and other lubricants; etc. Further, such tablets may be coated with typical coating materials as required, to prepare, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double- or multi-layered tablets, etc.
To form pills, any of various carriers conventionally known in this field can be used. Examples thereof include glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc, and other excipients; gum arabic powder, tragacanth powder, gelatin, ethanol, and other binders; laminarin, agar, and other disintegrators; etc.
To form suppositories, any of various carriers conventionally known in this field can be used. Examples thereof include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi synthetic glycerides, etc.
Capsules can be prepared by mixing the active principal compound with the above-mentioned carriers to enclose the former in a hard gelatin capsule, soft gelatin capsule or the like.
To form an injection, a solution, emulsion or suspension is sterilized and preferably made isotonic to blood. Any of the diluents widely used for such forms in this field can be employed to form the injection. Examples of such diluents include water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, fatty acid esters of polyoxyethylene sorbitan, etc.
In this case, the pharmaceutical preparation may contain sodium chloride, glucose or glycerol in an amount sufficient to prepare an isotonic solution, and may contain typical solubilizers, buffers, analgesic agents, etc. Further, if necessary, the pharmaceutical preparation may contain coloring agents, preservatives, flavors, sweetening agents, etc., and/or other medicines.
The amount of the compound represented by Formula (1) and the salt thereof included in the pharmaceutical preparation of the present invention is not limited, and can be suitably selected from a wide range. The proportion is generally about 0.1 to about 70 wt. %, preferably about 0.1 to about 30 wt. % of the pharmaceutical preparation.
The route of administration of the pharmaceutical preparation of the present invention is not particularly limited, and the preparation is administered by a route suitable to the form of the preparation, patient's age, sex and other conditions, and severity of the disease. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are intravenously administered singly or as mixed with typical injection transfusions such as glucose solutions, amino acid solutions or the like, or singly administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally, as required. Suppositories are administered intrarectally.
The dosage of the pharmaceutical preparation of the invention is suitably selected according to the method of use, patient's age, sex and other conditions, and severity of the disease. The amount of active principal compound is usually about 0.1 to about 10 mg/kg body weight/day. Further, it is desirable that the pharmaceutical preparation in each unit of the administration form contains the active principal compound in an amount of about 1 to about 200 mg.
The use of the compound of the present invention in combination with L-dopa preparations, dopamine receptor agonists, dopamine metabolism enzyme inhibitors, dopamine release-rate-promoting preparations, central anticholinergic agents, and the like can achieve effects such as dosage reduction, improvement of side effects, increased therapeutic efficacy, etc., which were not attained by known therapies.
Advantageous Effect of InventionThe compound of the present invention protect and improve mitochondrial function and/or protect neurons and repair neuronal function, and hence are effective in the treatment and/or prevention of neurodegenerative diseases, diseases induced by neurological dysfunction, and diseases induced by deterioration of mitochondrial function.
Examples of neurodegenerative diseases include Parkinson's disease, Parkinson's syndrome, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear palsy, pure akinesia, Alzheimer's disease, Pick's disease, prion disease, corticobasal degeneration, diffuse Lewy body disease, Huntington's disease, chorea-acanthocytosis, benign hereditary chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, Gilles de la Tourette's syndrome, Rett syndrome, degenerative ballism, dystonia musculorum deformans, athetosis, spasmodic torticollis, Meige syndrome, cerebral palsy, Wilson's disease, Segawa's disease, Hallervorden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy, spino-cerebellar degeneration, cerebral cortical atrophy, Holmes-type cerebellar atrophy, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, Joseph disease, dentatorubropallidoluysian atrophy, Gerstmann-Straussler-Scheinker disease, Friedreich's ataxia, Roussy-Levy syndrome, May-White syndrome, congenital cerebellar ataxia, hereditary episodic ataxia, ataxia telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, progressive spinal muscular atrophy, spinobulbar muscular atrophy, Werdnig-Hoffmann disease, Kugelberg-Welander disease, hereditary spastic paraparesis, syringomyelia, syringobulbia, Arnold-Chiari malformation, Stiff-man syndrome, Klippel-Feil syndrome, Fazio-Londe syndrome, lower myelopathy, Dandy-Walker syndrome, spina bifida, Sjogren-Larsson syndrome, radiation myelopathy, age-related macular degeneration, and cerebral apoplexy (e.g., cerebral infarction and cerebral hemorrhage) and/or dysfunction or neurologic deficits associated with cerebral apoplexy.
Examples of diseases induced by neurological dysfunction include spinal cord injury, chemotherapy-induced neuropathy, diabetic neuropathy, radiation damage, and demyelinating diseases (e.g., multiple sclerosis, acute disseminated encephalomyelitis, transverse myelitis, progressive multifocal leucoencephalopathy, subacute sclerosing panencephalitis, chronic inflammatory demyelinating polyneuropathy, and Guillain-Barre syndrome).
Examples of diseases induced by deterioration of mitochondrial function include Pearson's syndrome, diabetes, deafness, malignant migraine, Leber's disease, MELAS, MERRF, MERRF/MELAS overlap syndrome, NARP, pure myopathy, mitochondrial cardiomyopathy, myopathy, dementia, gastrointestinal ataxia, acquired sideroblastic anemia, aminoglycoside-induced hearing loss, complex III deficiency due to inherited variants of cytochrome b, multiple symmetrical lipomatosis, ataxia, myoclonus, retinopathy, MNGIE, ANT1 disease, Twinkle disease, POLG disease, recurrent myoglobinuria, SANDO, ARCO, complex I deficiency, complex II deficiency, optic nerve atrophy, fatal infantile complex IV deficiency, mitochondrial DNA deficiency syndrome, Leigh's encephalomyelopathy, chronic-progressive-external-ophthalmoplegia syndrome (CPEO), Kearns-Sayre syndrome, encephalopathy, lactacidemia, myoglobinuria, drug-induced mitochondrial diseases, schizophrenia, major depression disorder, bipolar I disorder, bipolar II disorder, mixed episode, dysthymic disorders, atypical depression, seasonal affective disorders, postpartum depression, minor depression, recurrent brief depressive disorder, intractable depression, chronic depression, double depression, and acute renal failure.
Furthermore, the compound of the present invention is effective in the prevention and/or treatment of ischemic heart diseases and/or associated dysfunction, cardiac failure, myocardosis, aortic dissection, immunodeficiency, autoimmune diseases, pancreatic insufficiency, diabetes, atheroembolic renal disease, polycystic kidney disease, medullary cystic disease, renal cortical necrosis, malignant nephrosclerosis, renal failure, hepatic encephalopathy, liver failure, chronic obstructive pulmonary disease, pulmonary embolism, bronchiectasis, silicosis, black lung, idiopathic pulmonary fibrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, muscular dystrophy, clostridial muscle necrosis, and femoral condyle necrosis.
The compound of the present invention can achieve effects heretofore unattained by known therapies, such as reduced dose, reduced side effects, and potentiated therapeutic effects, when it is administered in combination with L-dopa preparations, dopamine receptor agonists, dopamine metabolism enzyme inhibitors, dopamine release-rate-promoting preparations, central anticholinergic agents, cholinesterase inhibitors, N-methyl-D-aspartate glutamate receptor antagonists, or other agents used in thrombolytic therapy, cerebral edema therapy, brain protection therapy, antithrombotic therapy, and blood plasma dilution therapy.
DESCRIPTION OF EMBODIMENTSHereinafter, the present invention is described in more detail with reference to Reference Examples, Examples, and Pharmacological Test Examples.
Reference Example 1 4-Methyl-2-nitro-1-propoxybenzeneA DMF solution (4 ml) of potassium carbonate (5.21 g, 37.7 mmol) and 1-iodopropane (5.80 g, 34.1 mmol) was added to a N,N-dimethylformamide (DMF) solution (10 ml) of 4-methyl-2-nitrophenol (4.0 g, 26.1 mmol), and the mixture was stirred at room temperature for 48 hours. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution twice and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (n-hexane:ethyl acetate=9:1). The purified product was concentrated under reduced pressure to thereby obtain 4.23 g of pale-yellow oily 4-methyl-2-nitro-1-propoxybenzene (yield: 83%).
1H-NMR (CDCl3) δ ppm: 1.05 (3H, t, J=7.4 Hz), 1.80-1.86 (2H, m), 2.33 (3H, s), 4.02 (2H, t, J=6.4 Hz), 6.95 (1H, d, J=8.5 Hz), 7.29 (1H, d, J=8.5 Hz), 7.62 (1H, s).
Reference Example 2 5-Methyl-2-propoxyaniline4-Methyl-2-nitro-1-propoxybenzene (2.0 g, 10.2 mmol) and 5% palladium carbon (700 mg) were added to ethanol (30 ml), followed by conduction of catalytic reduction at room temperature under ordinary pressure. The catalyst was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and dried over anhydrous magnesium sulfate. The resultant dry substance was concentrated under reduced pressure to thereby obtain 1.49 g of reddish-brown oily 5-methyl-2-propoxyaniline (yield: 89%).
1H-NMR (CDCl3) δ ppm: 1.05 (3H, t, J=7.4 Hz), 1.76-1.86 (2H, m), 2.21 (3H, s), 3.73 (2H, brs), 3.91 (2H, t, J=6.5 Hz), 6.49-6.50 (1H, m), 6.54 (1H, s), 6.66 (1H, d, J=8.0 Hz).
Reference Example 3 Ethyl α-(hydroxymethylene)-4-methoxyphenyl acetateSodium hydride (60% in oil) (467 mg, 11.7 mmol) was added to a benzene solution (10 ml) of ethyl 4-methoxyphenyl acetate (2.0 g, 10.3 mmol), while being cooled with ice. The mixture was stirred at room temperature for 5 minutes. The stirred mixture was cooled with ice again; ethyl formate (1.02 ml, 12.6 mmol) was added thereto and stirred at room temperature for 3 hours. While being cooled with ice, water and ethyl acetate were added to the reaction mixture, and then 2N hydrochloric acid (6 ml) was added to separate the reaction mixture into two layers. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The purified product was concentrated under reduced pressure to thereby obtain 1.97 g of slightly reddish-brown oily ethyl α-(hydroxymethylene)-4-methoxyphenyl acetate (yield: 86%). The resulting object was purged with nitrogen and stored in a freezer.
1H-NMR (CDCl3) δ ppm: 1.28 (3H, t, J=7.1 Hz), 3.81 (3H, s), 4.28 (2H, q, J=7.1 Hz), 6.87 (2H, d, J=8.8 Hz), 7.16-7.26 (3H, m), 12.02 (1H, d, J=12.5 Hz).
Example 1270 mg of Amberlyst 15 (produced by Sigma-Aldrich Corporation) was added to a benzene solution (50 ml) of 5-methyl-2-propoxyaniline (1.49 g, 9.0 mmol) and ethyl α-(hydroxymethylene)-4-methoxyphenyl acetate (2.00 g, 9.0 mmol). The resulting mixture was heated under reflux for 6 hours using a Dean-Stark trap. The reaction mixture was then cooled to room temperature and filtered to remove resin. The filtrate was concentrated under reduced pressure. Diphenyl ether (2.5 ml) was added to the residue, and the mixture was then heated with a mantle heater and stirred for 50 minutes under reflux. The reaction mixture was cooled to room temperature, and then directly purified using silica gel column chromatography (dichloromethane:methanol=80:1→60:1). The purified product was concentrated under reduced pressure to recrystallize the residue from ethyl acetate, thereby giving 600 mg of pale-yellow scaly crystal 3-(4-methoxyphenyl)-5-methyl-8-propoxy-1H-quinolin-4-one (yield: 21%).
Melting point: 192° C.-193° C.
Using appropriate starting materials, Examples 2 to 109 were prepared in the same manner as in Example 1.
Example 2Melting point: 129° C.-131° C.
Example 3Melting point: 231° C.-233° C.
Example 41H-NMR (DMSO-d6) δ ppm: 1.35 (3H, t, J=6.8 Hz), 3.76 (3H, s), 4.23 (2H, q, J=6.9 Hz), 6.84-6.96 (4H, m), 7.64 (2H, d, J=8.6 Hz), 8.09 (1H, s), 8.11 (1H, d, J=8.8 Hz), 10.33 (1H, s).
Example 51H-NMR (DMSO-d6) δ ppm: 3.70 (3H, s), 3.76 (3H, s), 3.86 (3H, s), 3.93 (3H, s), 6.48 (1H, s), 6.95 (2H, d, J=8.8 Hz), 7.59 (2H, d, J=8.8 Hz), 8.22 (1H, s) 11.40 (1H, brs).
Example 61H-NMR (DMSO-d6) δ ppm: 0.90 (3H, t, J=7.2 Hz), 1.34-1.39 (2H, m), 1.55-1.59 (2H, m), 2.86 (2H, t, J=7.5 Hz), 3.76 (3H, s), 6.95 (2H, d, J=8.5 Hz), 7.25 (1H, t, J=7.7 Hz), 7.46 (1H, d, J=6.9 Hz), 7.62 (2H, d, J=8.5 Hz), 7.92 (1H, s), 8.08 (1H, d, J=8.0 Hz), 11.39 (1H, brs).
Example 71H-NMR (DMSO-d6) δ ppm: 0.94 (3H, t, J=7.2 Hz), 1.59-1.64 (2H, m), 2.83 (2H, t, J=7.5 Hz), 3.75 (3H, s), 6.93-6.95 (2H, m), 7.25 (1H, t, J=7.8 Hz), 7.46 (1H, d, J=6.0 Hz), 7.60-7.61 (2H, m), 7.92 (1H, s), 8.07-8.09 (1H, m), 11.40 (1H, brs).
Example 81H-NMR (DMSO-d6) δ ppm: 0.96 (3H, t, J=7.2 Hz), 1.59-1.66 (2H, m), 2.85 (2H, t, J=7.6 Hz), 7.27 (1H, t, J=7.9 Hz), 7.36 (2H, d, J=8.7 Hz), 7.49 (1H, d, J=7.0 Hz), 7.83 (2H, d, J=8.7 Hz), 8.02 (1H, s), 8.09-8.10 (1H, m), 11.47 (1H, brs).
Example 91H-NMR (DMSO-d6) δ ppm: 0.95 (3H, t, J=7.2 Hz), 1.58-1.65 (2H, m), 2.84 (2H, t, J=7.6 Hz), 7.27 (1H, d, J=7.9 Hz), 7.48 (1H, d, J=7.1 Hz), 7.55 (2H, d, J=8.5 Hz), 7.67 (2H, d, J=8.5 Hz), 8.00 (1H, s), 8.08-8.09 (1H, m), 11.46 (1H, brs).
Example 101H-NMR (DMSO-d6) δ ppm: 0.95 (3H, t, J=7.2 Hz), 1.59-1.66 (2H, m), 2.85 (2H, t, J=7.6 Hz), 3.81 (3H, s), 7.00 (2H, d, J=8.7 Hz), 7.28 (1H, t, J=8.5 Hz), 7.48 (1H, d, J=7.1 Hz), 7.60-7.64 (4H, m), 7.76 (2H, d, J=8.2 Hz), 8.02 (1H, s), 8.11 (1H, d, J=8.1 Hz), 11.45 (1H, brs).
Example 111H-NMR (DMSO-d6) δ ppm: 1.37 (3H, t, J=6.9 Hz), 3.91 (3H, s), 4.34 (2H, q, J=7.0 Hz), 7.01-7.04 (2H, m), 7.54 (2H, d, J=8.4 Hz), 7.69 (2H, d, J=8.4 Hz), 8.20 (1H, d, J=8.8 Hz), 8.24 (1H, s).
Example 121H-NMR (DMSO-d6) δ ppm: 1.38 (3H, t, J=7.0 Hz), 3.91 (3H, s), 4.35 (2H, q, J=7.0 Hz), 7.01-7.05 (2H, m), 7.34 (1H, t, J=7.4 Hz), 7.45 (2H, t, J=7.6 Hz), 7.65-7.68 (4H, m), 7.81 (2H, d, J=8.3 Hz), 8.22-8.25 (2H, m).
Example 13Melting point: 223° C.-224° C.
Example 143-(3,4-Dimethoxyphenyl)-8-propoxy-1H-quinolin-4-one
Pale-Yellow PowderMelting point: 210° C.-211° C.
Example 15Melting point: 259° C.-260° C.
Example 16Melting point: 231° C.-232° C.
Example 171H-NMR (DMSO-d6) δ ppm: 1.04 (3H, t, J=7.3 Hz), 1.78-1.90 (2H, m), 3.67 (3H, s), 3.84 (6H, s), 4.12 (2H, t, J=6.4 Hz), 7.00 (2H, s), 7.17-7.26 (2H, m), 7.74 (1H, d, J=6.7 Hz), 7.99 (1H, d, J=6.3 Hz), 11.47 (1H, d, J=6.2 Hz).
Example 18Melting point: 250° C.-251° C.,
Example 19Melting point: 214° C.-215° C.
Example 20Melting point: 193° C.-194° C.
Example 21Melting point: 113° C.-114° C.
Example 22Melting point: 186° C.-187° C.
Example 23Melting point: 174° C.-175° C.
Example 24Melting point: 220° C.-221° C.
Example 25Melting point: 182° C.-183° C.
Example 26Melting point: 159° C.-160° C.
Example 27Melting point: 189° C.
Example 28Melting point: 193° C.
Example 29Melting point: 230° C.
Example 30Melting point: 250° C.
Example 31Melting point: 175° C.
Example 32Melting point: 224° C.
Example 33Melting point: 160° C.
Example 34Melting point: 153° C.-154° C.
Example 35Melting point: 120° C.-121° C.
Example 36Melting point: 161° C.-162° C.
Example 37Melting point: 195° C.-196° C.
Example 38Melting point: 125° C.
Example 39Melting point: 218° C.-220° C.
Example 40Melting point: 239° C.-241° C.
Example 41Melting point: 253° C.-255° C.
Example 42Melting point: 145° C.-148° C.
Example 43Melting point: 179° C.-180° C.
Example 44Melting point: 255° C.-256° C.
Example 45Melting point: 117° C.-119° C.
Example 46Melting point: 213° C.-214° C.
Example 47Melting point: 242° C.-244° C.
Example 48Melting point: 160° C.-161° C.
Example 49Melting point: 169° C.-170° C.
Example 50Melting point: 201° C.-202° C.
Example 51Melting point: 130° C.-133° C.
Example 52Melting point: 221° C.-223° C.
Example 53Melting point: 170° C.-171° C.
Example 54Melting point: 200° C.-203° C.
Example 55Melting point: 107° C.-108° C.
Example 56Melting point: 81° C.-84° C.
Example 57Melting point: 103° C.-106° C.
Example 58Melting point: 104° C.-107° C.
Example 59Melting point: 189° C.-193° C.
Example 60Melting point: 110° C.-115° C.
Example 61Melting point: 104° C.-105° C.
Example 62Melting point: 106° C.-109° C.
Example 63Melting point: 80° C.-82° C.
Example 64Melting point: 81° C.-83° C.
Example 65Melting point: 168° C.-170° C.
Example 66Melting point: 90° C.-92° C.
Example 67Melting point: 196° C.-198° C.
Example 68Melting point: 177° C.-178° C.
Example 69Melting point: 182° C.-183° C.
Example 70Melting point: 132° C.-135° C.
Example 71Melting point: 258° C.-260° C.
Example 72Melting point: 159° C.-161° C.
Example 73Melting point: 260° C.-263° C.
Example 74Melting point: 265° C.-267° C.
Example 75Melting point: 270° C.-275° C. (decomposition)
Example 76Melting point: 186° C.-188° C.
Example 77Melting point: 214° C.-215° C.
Example 78Melting point: 191° C.-192° C.
Example 79Melting point: 198° C.-199° C.
Example 80Melting point: 156° C.-158° C.
Example 81Melting point: 145° C.-147° C.
Example 82Pale-Yellow Powder
Melting point: 198° C.-200° C.
Example 83Melting point: 99° C.-101° C.
Example 84Melting point: 249° C.-250° C.
Example 85Pale-Brown Powder
Melting point: 236° C.-237° C.
Example 86Melting point: 185° C.-186° C.
Example 87Melting point: 218° C.-220° C.
Example 88Melting point: 212° C.-214° C.
Example 89Melting point: 158° C.-160° C.
Example 90Melting point: 193° C.-195° C.
Example 91Melting point: 237° C.-239° C.
Example 92Melting point: 100° C.-101° C.
Example 93Melting point: 213° C.-215° C.
Example 94Melting point: 232° C.-234° C.
Example 95Melting point: 112° C.-113° C.
Example 96Melting point: 129° C.-131° C.
Example 97Melting point: 189° C.-190° C.
Example 98Melting point: 229° C.-231° C.
Example 99Melting point: 186° C.-187° C.
Example 100Melting point: 19-PC-199° C.
Example 101Melting point: 90° C.-93° C.
Example 102Melting point: 111° C.-113° C.
Example 103Melting point: 186° C.-187° C.
Example 104Melting point: 266° C.-268° C.
Example 105Melting point: 254° C.-256° C.
Example 106Melting point: 154° C.-155° C.
Example 107Melting point: 163° C.-165° C.
Example 108Melting point: 204° C.-206° C.
Example 109Melting point: 189° C.-190° C.
Pharmacological Test 1Evaluation of Improvement of Mitochondrial Function Using Human Neuroblastoma Cell Lines SH-SY5Y Treated with 1-Methyl-4-Phenylpyridinium (MPP+)
In human neuroblastoma cell lines SH-SY5Y in which mitochondrial function was damaged by MPP+ treatment (Bollimuntha S. et al., J Biol Chem, 280, 2132-2140 (2005) and Shang T. et al., J Biol Chem, 280, 34644-34653 (2005)), the improvement of mitochondrial function was evaluated on the basis of the measurement value for mitochondrial oxidation reduction activity using Alamar Blue fluorescent dye after the compound addition (Nakai M. et al, Exp Neurol, 179, 103-110 (2003)).
The human neuroblastoma cell lines SH-SY5Y were cultured in Dulbecco's Modified Eagle's Medium containing 10% fetal bovine serum (DMEM containing 50 units/ml penicillin and 50 μg/ml streptomycin as antibiotics) at 37° C. in the presence of 5% carbon dioxide. Cells were scattered on a poly-D-lysine-coated 96-well black plate at a concentration of 3−6×104 cells/cm2 (medium amount: 100 μl/well) and cultured in the medium for two days. Further, the medium was changed to DMEM containing a 1% N2 supplement (N2-DMEM) or to a medium (100 μl/well) in which 1.5 mM MPP+ was dissolved. The cells were cultured therein for 39 to 48 hours, and then subjected to a mitochondrial oxidation reduction activity measurement system. A sample compound that had been previously dissolved in dimethyl sulfoxide (DMSO) was diluted with N2-DMEM and added in a volume of 10 μl/well 24 hours before the activity measurement (final compound concentration: 0.01 to 1 μg/ml).
After removal of the medium by suction, a balanced salt solution containing 10% Alamar Blue (154 mM sodium chloride, 5.6 mM potassium chloride, 2.3 mM calcium chloride, 1.0 mM magnesium chloride, 3.6 mM sodium hydrogen carbonate, 5 mM glucose, 5 mM HEPES, pH 7.2) was added in a volume of 100 μl/well, and reacted in an incubator at 37° C. for 1 hour. The fluorescent intensity was detected using a fluorescence detector (a product of Hamamatsu Photonics K.K., excitation wavelength: 530 nm, measurement wavelength: 580 nm) to thereby measure the mitochondrial oxidation reduction activity.
The fluorescent intensity of the well of the cells cultured in a medium containing MPP+ and each of the sample compounds was relatively evaluated based on the 100% fluorescent intensity of the well of the cells cultured in a medium containing DMSO alone (final concentration: 0.1%). When the MPP+ -induced cell group exhibited higher florescent intensity than the cell group cultured in DMSO alone, the test compound was judged to have improved the mitochondrial function.
Evaluation of Dopaminergic Neuronal Protective Activity Using C57BL/6 Mouse Treated with 1-Methyl-4-Phenyl 1,2,3,6-Tetrahydro Pyridine (MPTP)
Using a mouse having MPTP-induced dopaminergic neurons (Chan P. et al., J Neurochem, 57, 348-351 (1991)), the dopaminergic neuronal protective activity was evaluated based on the protein levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT), which are dopaminergic neuronal marker proteins, and a dopamine content in the brain corpus striatum region after the compound administration (Mori A. et al., Neurosci Res, 51, 265-274 (2005)).
A male C57BL/6 mouse (provided by Japan Charles River Inc., 10 to 12 weeks) was used as a test animal. MPTP was dissolved in a physiological salt solution so that the concentration was 4 mg/ml, and then administered to the mouse subcutaneously in a volume of 10 ml/kg. A test compound was suspended in a 5% gum arabic/physiological salt solution (w/v) so that the concentration was 1 mg/ml. Each of the test compounds or solvents thereof was orally administered to the mouse after 30 minutes, 24 hours, and 48 hours of the MPTP administration. The mouse was decapitated after 72 hours of the MPTP administration, the brain was removed, and each side of the striatum was dissected.
The left striatum was used as a sample to detect the protein level by Western blot analysis. Each tissue was homogenized in a HEPES buffer sucrose solution (0.32 M sucrose, 4 μg/ml pepstatin, 5 μg/ml aprotinin, 20 μg/ml trypsin inhibitor, 4 μg/ml leupeptin, 0.2 mM phenylmethanesulfonyl fluoride, 2 mM ethylenediaminetetraacetic acid (EDTA), 2 mM ethylene glycol bis (β aminoethyl ether) tetraacetic acid, 20 mM HEPES, pH 7.2), and assayed for protein using a bicinchoninic acid kit for protein assay (provided by Pierce Corporation). Each homogenized sample, having an equal amount of protein that had been dissolved in a Laemmli sample buffer solution, was subjected to electrophoresis through a sodium dodecyl sulfate polyacrylamide gel. The protein separated by electrophoresis was electrically transferred to polyvinylidene fluoride membrane. The membrane was reacted with a specific primary antibody for TH, DAT, and housekeeping proteins, i.e., α1 subunit of Na+/K+-ATPase and actin (Na+/K+-ATPase is a product of Upstate Biotechnology Inc.; others are products of Chemi-Con Corporation). Subsequently, a horseradish peroxidase-labeled secondary antibody (a product of Amersham K.K.) for each primary antibody was fixed, and the chemiluminescence associated with enzyme activity of peroxidase was detected using a X-ray film. The density of the protein band on the film was analyzed using a densitometer (a product of Bio-rad Laboratories Inc.) to obtain the TH value relative to Na+/K+-ATPase and the DAT value relative to actin.
The right striatum, the tissue weight of which was measured immediately after dissection, was used as an analysis sample for determining the dopamine content. Each tissue was homogenized in a 0.1 N perchloric acid solution containing isoproterenol as an internal standard substance of the measurement, using an ultrasonic homogenizer while being cooled with ice. The supernatant obtained from 20,000 g of homogenate that had been centrifuged at 4° C. for 15 minutes was subjected to a high-performance liquid chromatography with a reversed phase column (a product of Eicom Corporation). A mobile phase 15% methanol 0.1 M citric acid/0.1 M sodium acetate buffer solution (containing 190 mg/L1-sodium octane sulfonate and 5 mg/L EDTA, pH 3.5) was flowed at a rate of 0.5 ml/min, and the dopamine peak of each sample was detected using an electrochemical detector (applied voltage: +750 mV vs. Ag/AgCl, a product of Eicom Corporation). With reference to the identified dopamine peak, the dopamine content per tissue weight was calculated in each sample using analysis software (a product of Gilson Inc.).
In both analyses, the value of the sample derived from the MPTP-induced mouse in which only the test compound or the solvent was administered was expressed relative to the value of the sample derived from the mouse without MPTP treatment (100%). Values were analyzed statistically using a nonclinical statistical analysis system, and values of significance probability less than 0.05 were defined as significant. In the MPTP-induced mouse, when the test drug group showed an increase in protein level compared to the solvent group, and a significant difference was observed between these groups in the t-assay, the test drug was judged to have dopamine neuroprotective activity.
Claims
1. A therapeutic and/or prophylactic agent for neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases induced by deterioration of mitochondrial function, the agent comprising as an active ingredient a quinolone compound represented by Formula (1): or a salt thereof, wherein: (1) lower alkyl, (2) halogen-substituted lower alkyl, (3) hydroxy, (4) lower alkoxy, (5) halogen-substituted lower alkoxy, (6) phenyl optionally having one or more substituents selected from the group consisting of lower alkyl and lower alkoxy, and (7) halogen; (1) hydrogen, (2) hydroxy, (3) lower alkyl, (4) lower alkoxy, (5) phenoxy, (6) cyclo C3-C8 alkyloxy, (7) halogen, (8) lower alkylthio, (9) amino optionally having one or two substituents selected from the group consisting of lower alkyl, lower alkoxy lower alkyl, and cyclo C3-C8 alkyl, (10) carbamoyl optionally having one or two lower alkyl groups, (11) pyrrolidinyl, (12) azepanyl, (13) morpholinyl, (14) piperazinyl optionally having one or two lower alkyl groups, (15) imidazolyl optionally having one or two lower alkyl groups, (16) furyl, (17) thienyl, (18) benzothienyl, and (19) pyrrolidinylcarbonyl.
- R1 represents hydrogen, lower alkyl, or cyclo C3-C8 alkyl lower alkyl;
- R2 represents hydrogen or lower alkyl; and
- R3 represents phenyl, naphthyl, pyridyl, furyl, thienyl, indolyl, benzodioxolyl or benzothienyl, wherein the aromatic or heterocyclic ring represented by R3 may be substituted with one or more substituents selected from the group consisting of the following substituents (1) to (7):
- R4 represents hydrogen, lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkoxy, lower alkoxy lower alkyl, phenyl, cyclo C3-C8 alkyl, or carbamoyl optionally having one or two lower alkyl groups;
- R5 represents hydrogen, lower alkyl, halogen, lower alkoxy, benzoylamino, or imidazolyl,
- R6 represents hydrogen, halogen, lower alkyl, hydroxy, or lower alkoxy; and
- R7 represents any of the following groups (1) to (19):
2. A therapeutic and/or prophylactic agent according to claim 1, wherein the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Parkinson's syndrome, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear palsy, pure akinesia, Alzheimer's disease, Pick's disease, prion disease, corticobasal degeneration, diffuse Lewy body disease, Huntington's disease, chorea-acanthocytosis, benign hereditary chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, Gilles de la Tourette's syndrome, Rett's syndrome, degenerative ballism, dystonia musculorum deformans, athetosis, spasmodic torticollis, Meige syndrome, cerebral palsy, Wilson's disease, Segawa's disease, Hallervorden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy, spinocerebellar degeneration, cerebral cortical atrophy, Holmes-type cerebellar atrophy, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, Joseph disease, dentatorubropallidoluysian atrophy, Gerstmann-Straussler-Scheinker disease, Friedreich's ataxia, Roussy-Levy syndrome, May-White syndrome, congenital cerebellar ataxia, hereditary episodic ataxia, ataxia telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, spinal progressive muscular atrophy, spinobulbar muscular atrophy, Werdnig-Hoffmann disease, Kugelberg-Welander disease, hereditary spastic paraparesis, syringomyelia, syringobulbia, Arnold-Chiari malformation, Stiff-man syndrome, Klippel-Feil syndrome, Fazio-Londe syndrome, lower myelopathy, Dandy-Walker syndrome, spina bifida, Sjogren-Larsson syndrome, radiation myelopathy, age-related macular degeneration, and cerebral apoplexy selected from the group consisting of cerebral infarction and cerebral hemorrhage and/or associated dysfunction or neurologic deficits.
3. A therapeutic and/or prophylactic agent according to claim 1, wherein the disease induced by neurological dysfunction is selected from the group consisting of spinal cord injury, chemotherapy-induced neuropathy, diabetic neuropathy, radiation damage, and a demyelinating disease selected from the group consisting of multiple sclerosis, acute disseminated encephalomyelitis, transverse myelitis, progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis, chronic inflammatory demyelinating polyneuropathy, and Guillain-Barre syndrome.
4. A therapeutic and/or prophylactic agent according to claim 1, wherein the disease induced by deterioration of mitochondrial function is selected from the group consisting of Pearson's syndrome, diabetes, deafness, malignant migraine, Leber's disease, MELAS, MERRF, MERRF/MELAS overlap syndrome, NARP, pure myopathy, mitochondrial cardiomyopathy, myopathy, dementia, gastrointestinal ataxia, acquired sideroblastic anemia, aminoglycoside-induced hearing loss, complex III deficiency due to inherited variants of cytochrome b, multiple symmetric lipomatosis, ataxia, myoclonus, retinopathy, MNGIE, ANT1 disease, Twinkle disease, POLG disease, recurrent myoglobinuria, SANDO, ARCO, complex I deficiency, complex II deficiency, optic nerve atrophy, fatal infantile complex IV deficiency, mitochondrial DNA deficiency syndrome, Leigh's encephalomyelopathy, chronic progressive external ophthalmoplegia syndrome (CPEO), Kearns-Sayre syndrome, encephalopathy, lactacidemia, myoglobinuria, drug-induced mitochondrial diseases, schizophrenia, major depression disorder, bipolar I disorder, bipolar II disorder, mixed episode, dysthymic disorders, atypical depression, seasonal affective disorders, postpartum depression, minor depression, recurrent brief depressive disorder, intractable depression, chronic depression, double depression, and acute renal failure.
5. A therapeutic and/or prophylactic agent comprising as an active ingredient a quinolone compound represented by Formula (1) of claim 1 or a salt thereof, the agent being used for treating or preventing ischemic heart diseases and/or associated dysfunction, cardiac failure, myocardosis, aortic dissection, immunodeficiency, autoimmune diseases, pancreatic insufficiency, diabetes, atheroembolic renal disease, polycystic kidney, medullary cystic disease, renal cortical necrosis, malignant nephrosclerosis, renal failure, hepatic encephalopathy, liver failure, chronic obstructive pulmonary disease, pulmonary embolism, bronchiectasis, silicosis, black lung, idiopathic pulmonary fibrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, muscular dystrophy, clostridial myonecrosis, and femoral condyle necrosis.
6. A method for treating and/or preventing neurodegenerative diseases, diseases induced by neurological dysfunction, or diseases induced by deterioration of mitochondrial function, the method comprising administering a quinolone compound represented by Formula (1) of claim 1 or a salt thereof to a human or an animal.
Type: Application
Filed: Dec 4, 2009
Publication Date: Oct 13, 2011
Applicant: OTSUKA PHARMACEUTICAL CO., LTD. (Chiyoda-ku, Tokyo)
Inventors: Kenji Otsubo (Osaka-shi), Yuji Ochi (Osaka-shi), Masami Nakai (Osaka-shi), Atsushi Mori (Osaka-shi), Takayuki Matsuzaki (Osaka-shi)
Application Number: 13/128,803
International Classification: A61K 31/47 (20060101); C07D 215/22 (20060101); C07D 215/233 (20060101); C07D 401/04 (20060101); A61K 31/4709 (20060101); C07D 215/38 (20060101); C07D 405/10 (20060101); C07D 409/04 (20060101); C07D 401/10 (20060101); C07D 413/10 (20060101); A61K 31/5377 (20060101); A61K 31/496 (20060101); A61K 31/55 (20060101); A61P 25/00 (20060101); A61P 9/10 (20060101); A61P 1/16 (20060101); A61P 37/02 (20060101); A61P 9/00 (20060101); A61P 3/10 (20060101); A61P 11/00 (20060101); C07D 215/26 (20060101);
